학술논문
Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication
Document Type
Academic Journal
Author
Tsukamoto, Yuta; Hiono, Takahiro; Yamada, Shintaro; Matsuno, Keita; Faist, Aileen; Gaff, Tobias; Hou, Jianyu; Namasivayam, Vigneshwaran; vom Hemdt, Anja; Sugimoto, Satoko; Ng, Jin Ying; Christensen, Maria H.; Tesfamariam, Yonas M.; Wolter, Steven; Juranek, Stefan; Zillinger, Thomas; Bauer, Stefan; Hirokawa, Takatsugu; Schmidt, Florian I.; Kochs, Georg; Shimojima, Masayuki; Huang, Yi-Shuian; Pichlmair, Andreas; Kummerer, Beate M.; Sakoda, Yoshihiro; Schlee, Martin; Brunotte, Linda; Miiller, Christa E.; Igarashi, Manabu; Kato, Hiroki
Source
Science. February 10, 2023, Vol. 379 Issue 6632, p586, 6 p.
Subject
Language
English
ISSN
0036-8075
Abstract
Orthomyxo- and bunyaviruses steal the 5' cap portion of host RNAs to prime their own transcription in a process called 'cap snatching.' We report that RNA modification of the cap portion by host 2'-0-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from Sfrepfomyces, called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its S-adenosyl-L-methionine binding pocket to restrict influenza virus replication. Mechanistically, TFMT impairs the association of host cap RNAs with the viral polymerase basic protein 2 subunit in human lung explants and in vivo in mice. TFMT acts synergistically with approved anti-influenza drugs.